Breast cancer is a heterogeneous disease with several subtypes identified by unique molecular signatures. Nearly, 30% of total breast cancer patients overexpress human epidermal growth factor receptor 2 (ErbB2 or HER2). HER2 is a receptor tyrosine kinase and is associated with poor prognosis and outcome. It is well documented that overexpression of HER2 promotes aggressive tumor phenotype, increases metastasis and decreases overall survival of patients.
Trastuzumab, a monoclonal antibody to HER2, accrues significant clinical benefit in the metastatic and adjuvant settings. However, some patients suffer disease recurrence despite adjuvant trastuzumab therapy, and many patients with metastatic disease do not respond to therapy or develop refractory disease within 1 year of treatment.
Dysregulation of several microRNAs (miRNAs) is also known to play a role in breast cancer progression and metastasis. MicroRNAs are small (18-25 nucleotide) long non-coding, single stranded RNAs that regulate the expression of various genes at post-transcriptional level mostly by binding to a partially complementary site on the 3′UTR region of target mRNA. It has been suggested that HER2 regulates the expression of certain miRNAs to promote cell proliferation and tumorigenesis. For instance, down-regulation of miR-205 by HER2 has been shown to enhance tumorigenesis in breast cancer. It has also been found that hyper-methylation of miR-200b promoter is associated with higher HER2 expression, and aberrant expression of some miRNAs by HER2 has been shown to enhance resistance to chemotherapeutic drugs. However, it still remains largely unknown how HER2 promotes tumor progression via regulation of specific microRNAs as well as other miRNAs that may be involved in the process.
What are needed in the art are methods and materials for use in diagnosis and treatment of breast cancer. For instance, identification of specific molecular factors that can regulate HER2 signaling would be of great benefit for more targeted and efficient therapy against many breast cancers including HER2 positive breast cancer.